The principle objective of this research is to learn how myocardial cells react to lethal and non lethal ischemic injury and to determine what event, or series of events, dictates that injury is irreversible. The studies proposed are designed to determine the relationships between depletion of high energy phosphate, the accumulation of ischemic catabolites (osmolar load) and the onset of irreversibility. Our goal is to establish if there is a causal relationship between either ATP depletion or metabolite accumulation and cell death in ischemia and to establish the mechanism by which either or both of these changes kill the myocytes. We postulate that disruption of the plasmalemma of the sarcolemma during ischemia is the lethal change from which the myocyte cannot recover and we therefore will attempt to elucidate the pathogenesis of plasmalemmal damage in ischemia and/or early reperfusion, i.e., lethal reperfusion injury. We plan to investigate the role of cell swelling by testing whether preventing cell swelling while the tissue is ischemic and/or during reperfusion will prevent the death of myocytes destined to die if reperfused with arterial blood. Finally, the molecular mechanisms underlying the capacity of the myocardium to adapt to ischemia, i.e., the ischemic preconditioning phenomenon, also will be investigated. One postulated mechanism involves changes in the degree of, and/or speed of inhibition of the mitochondrial ATPase by the endogenous inhibitor found in the matrix space of the mitochondria. (The mitochondrial ATPase is the enzyme which squanders 30- 50% of the ATP expended while the tissue is ischemic). We propose to investigate whether the reduced demand for ATP found in preconditioning involves depressed ATPase activity. An alternate hypothesis to explain the protective effect of preconditioning is that it is mediated by activation of A1 adenosine receptors. We plan to investigate this hypothesis in the intact ischemic dog heart, paying particular attention to the question of whether activation of the receptor induces the metabolic changes characteristic of ischemia and, if it does, how it does it.